A Randomized, Placebo-Controlled Study of Romosozumab for the Treatment of Hip Fractures

Abstract

Background: Romosozumab is a bone-forming antibody that increases bone formation and decreases bone resorption. We conducted a double-blinded, randomized, phase-2, dose-finding trial to evaluate the effect of romosozumab on the clinical outcomes of open reduction and internal fixation of intertrochanteric or femoral neck hip fractures.

Methods: Patients (55 to 94 years old) were randomized 2:3:3:3 to receive 3 subcutaneous injections of romosozumab (70, 140, or 210 mg) or a placebo postoperatively on day 1 and weeks 2, 6, and 12. The primary end point was the difference in the mean timed "Up & Go" (TUG) score over weeks 6 to 20 for romosozumab versus placebo. Additional end points included the time to radiographic evidence of healing and the score on the Radiographic Union Scale for Hip (RUSH).

Results: A total of 332 patients were randomized: 243 to receive romosozumab (70 mg, n = 60; 140 mg, n = 93; and 210 mg, n = 90) and 89 to receive a placebo. Although TUG scores improved during the study, they did not differ significantly between the romosozumab and placebo groups over weeks 6 to 20 (p = 0.198). The median time to radiographic evidence of healing was 16.4 to 16.9 weeks across treatment groups. The RUSH scores improved over time across treatment groups but did not differ significantly between the romosozumab and placebo groups. The overall safety and tolerability profile of romosozumab was comparable with that of the placebo.

Conclusions: Romosozumab did not improve the fracture-healing-related clinical and radiographic outcomes in the study population.

Level of evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Fig. 1

Study schema. Randomization was stratified into 7 strata: (1) intertrochanteric fracture, sliding hip screw, 55 to 75 years old; (2) intertrochanteric fracture, sliding hip screw, ≥76 years old; (3) intertrochanteric fracture, intramedullary nail, 55 to 75 years old; (4) intertrochanteric fracture, intramedullary nail, ≥76 years old; (5) displaced femoral neck fracture, sliding hip screw; (6) displaced femoral neck fracture, cancellous screws; and (7) undisplaced femoral neck fracture. Within each stratum, patients were randomized using an allocation ratio of 2:3:3:3 to receive subcutaneous injections of romosozumab (70, 140, or 210 mg) or a placebo. The placebo group received 3 vials of placebo solution; the 70-mg group, 1 vial containing 70 mg of romosozumab and 2 vials of matched placebo solution; the 140-mg group, 2 vials each containing 70 mg of romosozumab and 1 vial of matched placebo solution; and the 210-group, 3 vials each containing 70 mg of romosozumab. Black arrows indicate study visits with administration of the investigational product, gray arrows indicate study visits without administration of the investigational product, and brown arrows indicate telephone visits. D = day, SC = subcutaneous, W = week.

Fig. 2

Flow of patients through the study. SC = subcutaneous.

Fig. 3

TUG scores by visit. Estimates are based on a linear mixed-effects model for repeated measures, adjusting for treatment, sex, prefracture community-dwelling status, prefracture walking aid use, geographic region (group 1: Greece, India, Italy, and Lithuania; group 2: Switzerland, Denmark, Estonia, Finland, Latvia, the Netherlands, Hungary, and New Zealand; group 3: Argentina, Australia, Belgium, Bulgaria, Canada, Germany, U.K., Hong Kong, Poland, and U.S.), quality of surgical fixation, visit, treatment-by-visit interaction, and randomization strata. Log-transformed scores were back-transformed to seconds using the exponential transformation. The results are presented as LSMs with 95% CIs. The p value is based on an F test of multilinear contrasts at weeks 6 to 20.

Fig. 4

RUSH scores by visit. N = number of randomized patients who received ≥1 dose of investigational product. The results are presented as the mean and standard deviation (SD). The dashed line represents the maximum total RUSH score (30 points).